Are all thiazides created equal?

At the Brigham Renal Board Review course (review of board prep options) a few weeks ago, Dr Burton Rose argued that for all of us who use thiazide diuretics (review of thiazides) to treat mild hypertension, chlorthalidone should be used instead of hydrochlorothiazide. I tend to like HCTZ as a blood pressure agent because of its cost and availability in combination pills, so I decided to look into the evidence for one thiazide over the other in order to make an informed choice. Here are the arguments for each:

Chlorthalidone, tested and true: chlorthalidone has been the thiazide used in many clinical trials, most notably ALLHAT, showing morbidity and mortality benefit from blood pressure control. HCTZ has a much shorter track record. Chlorthalidone also has a much longer half-life (45-50 hours, compared to 8-15 hours for HCTZ), so putatively it should provide a more sustained effect.

HCTZ, does the job and my drugstore stocks it: HCTZ has been shown in clinical trials to be effective in reducing blood pressure, and remains the most readily available thiazide in pharmacies. It exists in many combination pills, which are also extremely affordable. There is a small amount of data suggesting that HCTZ causes less hypokalemia than chlorthalidone, but results are mixed.

How did they match up head to head? Naturally, the definitive study is still waiting for an enterprising renal fellow to come along and take charge. There have been two studies that indicate chlorthalidone might be the more efficacious agent.

1. As part of the MRFIT (Multiple Risk Factor Intervention Trial) trial, first published in the 1980s, physicians were initially given the option of HCTZ or chlorthalidone as the step 1 diuretic in the treatment group. After five years of the study, however, the protocol was changed to recommend only chlorthalidone, given a significant mortality benefit compared to participants on HCTZ.
   
2. The only trial comparing the two drugs head to head, with the primary purpose of assessing blood pressure reduction, was published in 2006 by Ernst et al. The trial was a single-blinded crossover study assessing the antihypertensive effects of HCTZ 25 mg daily (force-titrated to 50 mg/d) versus chlorthalidone 12.5 mg/d (force-titrated to 25 mg/d). After eight weeks, the chlorthalidone group showed a significantly greater reduction in 24h ambulatory blood pressure compared to HCTZ, with most of the difference occurring in nighttime BP measurements. Interestingly, a significant order-drug-time interaction was found, so the second half of the crossover study was not analyzed. Hypokalemia rates were similar in the two groups.

In my mind, it seems reasonable to choose chlorthalidone over HCTZ in patients for whom adding a thiazide to their antihypertensive regimen is appropriate. For those who are stable on HCTZ, the hassle of rechecking potassium levels after switching agents may not be worth the potential benefits. For those patients who require more than one BP agent (most of our patients), and especially ACE inhibition, the HCTZ-lisinopril combo is an attractive and inexpensive option that is hard to beat.

Nate discussed thiazide side effects, including hyperglycemia on a prior post. Conall discusses hyponatremia as a side effect.

Get it right …the first time

The whole fiasco about the antenna and reception issue with the iPhone 4 made me realize that unlike other professions, where several chances exist to rectify a problem, clinicians often have only one chance to get it right while caring for patients. This would apply particularly well in the management of patients with hemolytic uremic syndrome (HUS).

Diarrhea associated HUS (typical HUS) occurs more commonly in children with annual incidence of 3-5 cases/100000 and is most commonly caused by shiga-like toxin producing bacteria, notably O157:H7 strains of Enterohemorrhagic Escherichia coli (EHEC), though newer strains have being reported. Diagnosis is often confirmed by stool cultures but may be negative in 15% patients. These individuals often recover without any sequelae. Kidney transplantation offers excellent patient and graft survival in 3% patients who progress to develop end stage renal disease (ESRD).

On the flip side, atypical HUS is more frequently seen in adults and is commonly due to mutations involving complement factor H (CFH), I (CFI) and membrane complex protein (MCP). These are glycoproteins synthesized in the liver and play a major role in stabilizing the C3 convertase of the alternate complement pathway. Mutations in the genes that encode these plasma proteins and complement components (C3 and factor B) leads to unregulated activation of the alternate complement pathway, thereby precipitating atypical HUS. Low C3 levels therefore serve as a clue to the presence of atypical HUS in these patients.

Unlike typical HUS, patients with atypical HUS have high (25%) mortality, with progression to ESRD in up to 50-60%. Nate had a nice discussion about the use of Eculizumab (anti complement factor C5) in atypical HUS. Kidney transplantation (see recent review for more information) have variable outcomes in this subgroup, and in fact, live related donor kidney transplantation is contraindicated in patients with CFH and CFI mutations due to increased risk of occurrence of HUS in the donor and 80-90% chance of recurrence in the recipient in first 6 months following transplant.

Due to such varied outcomes, it is essential that the correct cause of HUS is identified at the time of presentation. It should be noted that presence or absence of diarrhea to differentiate these two types is not reliable and up to 20% patients with atypical HUS may have diarrhea as their symptom.Also, not all cases of atypical HUS have a family history of the disease. Correct diagnosis can therefore only be made if evaluation of patients with HUS includes assays for CFH, CFI, MCP, C3 and factor B at the time of diagnosis and prior to initiation of plasma exchange therapy in addition to routinely done tests such as stool studies for EHEC, shigella, campylobacter and salmonella, lupus serologies C3, C4, and ADAMTS 13 activity levels. Accurate identification of the cause of HUS can help the nephrologists in identifying patients who may or may not benefit from kidney transplantation and also for offering other treatment options such as combined liver and kidney transplantation for CFH/CFI mutations with pre operative plasma exchange and isolated kidney transplantation with preoperative plasma exchange for MCP mutations.

So, the next time you are consulted for management of patients with HUS, make sure you get it right...the first time.

Viresh Mohanlal, MD

Board question: Water-1 answer

This was an actual case I saw and thought it generated a multitude of interesting dilemmas. When I initially examined the patient she was in status epilepticus. This, by itself, mandated the immediate correction of her serum sodium. But what was the best way to achieve the correction without adversely affected the patient? This was my thought process…

The patient is 100kg women, so her TBW should be 50 Liters. (using the Watson Formula)

I decided to separate her water and solute gains/losses to determine what her total body sodium was at that instance.

She had already received 2L of normal saline but lost 3L in urine, so net water loss of 1L. 1L of free water loss would cause that serum sodium to rise 2.5meq/L.

Calculation: 120 (desired Na)-115 (actual Na)/120 (desired Na) times 50L (TBW) is equal to roughly 2L. Therefore, 2L of free water loss would raise serum sodium 5 meq/L.

Therefore, for each 1L of water loss, the serum sodium would rise 2.5 meq/L. (5meq/L divided by 2)

So, just based on water loss, her serum sodium has risen 2.5 meq/L already, so the serum sodium is 117.5 meq/L. Next, I calculated the impact of solute gain. Total solute for a 100kg woman with a serum sodium of 115 would be 5750 (50L times 115meq/L). I estimated that she gained 133 meq of solute… INPUT: 2L of normal saline 388meq KCL 80meq Total input 468 meq solute input LOSS: Urine sodium of 75 meq/L times 3L urine output is 225 meq Urine potassium of 10 meq/L times 3L urine output is 30 meq Total loss: 255meq

So, total solute input (388)-total solute output (255) equals a gain of 133meq of solute.

How does this impact the serum sodium? Total body solute 5750 plus gain of 133 equals 5865 5865 meq (New Total Body Solute) divided by TBW (50 L) equals 117.3 Therefore, serum sodium rose 2.3 based on solute gain alone.

If you add the affect of free water loss and solute gain, I anticipated that the serum sodium at that instance was 120 meq/L (2.5 meq/L from water loss and 2.3 from solute gain plus starting sodium of 115). So, I thought that the serum sodium was already in the “safe” zone and that the seizures were related to alcohol withdrawl.

I decided NOT to use 3% saline, and continue with gentle potassium repletion at that time (depite the intensivist’s insistence). What this physician failed to realize was that KCl has the same osmotic potential as sodium!

In fact, there are case reports of central pontine myelinosis induced by rapid correction of hyponatremia via potassium repletion alone.

The patient’s repeat sodium was 121! Her serum sodium stabilized over the coarse of a few days with mere potassium repletion. Her seizures persisted and patient eventually required anti-epileptic therapy.

Given the complexities of this case, there is not a perfect strategy for management. The purpose was to generate thoughts and discussions on the intricacies of hyponatremia management. Would you have managed her differently? Let me know your thoughts…

Michael Lattanzio, DO

This isn’t meant to be happening…

A paradigm of modern genetic studies, such as GWAS, is that there is a natural balance to allelic variation, with common variation in the population conferring mild disease risk and, conversely, genes of strong disease effect being rare. This phenomenon is formally described by the ‘common disease/ common variant’ (CDCV) and ‘multiple rare variant’ (MRV) models. The CDCV model predicts the existence of common genetic variants (present in 5–50%) that confer low to modest disease risk (e.g relative risks of 1.1–1.5). Complementing this is the MRV model, which holds that complex traits result from many different mutations, each of which is individually rare (a few percent at most and perhaps orders of magnitude less common), but with very strong effect (for example, relative risks 5 – 10, or even more; see figure). This phenomenon is thought to explain why the search for causative genes derived from GWA studies has been relatively unsuccessful, where only a handful of causative genes have been discovered in follow-up sequencing studies. It is assumed that this difficulty in finding culprit genes is due to these modest effects making them difficult to recognize. Undiscovered common genes of strong effect are simply not thought to exist…

So what is going on in Nephrology? Within the space of a few short weeks there have been 2 separate, high quality studies identifying common disease-causing gene polymorphisms of very strong effect. First, there was the identification of 2 independent APOL1 variants, present in over 30% of African-American chromosomes, that carry odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. Analagous to HgbS-mediated protection from malaria, these APOL1 risk variants appear to have risen to very high frequency in Africa as they cause resistance to trypanosomal infection, thus protecting from sleeping sickness. Although the mechanism by which APOL1 variants cause kidney disease are not known, the mechanism of trypanosomal resistance has been described, and offers the hope for a new treatment of this life-threatening infection.

And now this morning, investigators from Hong Kong, reporting in JAMA, describe finding another set of common gene polymorphisms of strong effect. This candidate gene study of Chinese patients with type 2 diabetes, identified several variants of the PRKCß 1 gene as being associated with incident ESRD and, in a follow-up analysis, CKD. The adjusted risk for ESRD was 6.04 (95% CI, 2.00-18.31) for individuals with 4 risk alleles compared with those with 0 or 1, and allele frequencies were high (7-12.2%). PRKCß 1 is an excellent candidate for kidney disease risk in diabetes, with a prior RCT of blockade of its gene-product, PKC-ß, demonstrating slowed disease progression and reduced proteinuria in diabetic patients already on maximal medical therapy.


So, recent studies in Nephrology are bucking the trend in genetic epidemiology, and challenging one of its most basic hypotheses. Whether this is because the assumptions themselves are flawed, or that Nephrology research is just catching up with other fields, remains to be seen.

Board question of the week: Water-1

A 40-year-old woman is rushed to ER for change in mental status. She has a history of multiple sclerosis and alcohol abuse. On arrival to ER, she exhibits 3 stereotyped, tonic-clonic seizure that resolve with ativan. The initial metabolic panel is listed below:

Na- 115, K- 1.6, Cl- 56, HCO3- 40, BUN- 10, Cr- 0.8, Serum osmolality- 240 Her husband arrives at the ER and reports heavy alcohol use over the last few weeks. He brings her medication list, which includes: Protonix, Tysabri (natalizumab, anti-alpha-4-integrin antibody), and Prednisone. Blood work from 3 months prior show a normal sodium level. She received 2L of normal saline in the ER, 80 meq of KCl, and one dose of lasix. Her urine output has been 3L so far. Urine electrolytes are obtained (Una 75, Uk 10). She weighs 100kg and on examination the patient is noted to be in “status”. Nephrology is consulted for the management of her hyponatremia.

How should this patient be managed acutely?Possible answers are listed in the poll on the upper right hand column.

The answer and explanation will be posted on Friday August 27th

Michael Lattanzio DO

*RFN board questions are meant to help introduce concepts about nephrology related diseases and do not represent actual questions seen on the ABIM exam.

Shaken not stirred...

Not long ago while on call I received a midnight consult for hyperkalemia. The patient had a history notable for CLL, who was electively admitted to  for induction chemotherapy. Prior to this admission, he had received no previous chemotherapeutic agents. On arrival to the floor he was found to have a potassium of 6.5 mmol/L, and received IV insulin, kayexalate, and albuterol for medical management. Reportedly he had no EKG changes at that time. Despite this medical management, repeat labs that night demonstrated a K of 9.3 with ‘some hemolysis’, which prompted an urgent renal consult from an understandably concerned intern.

After waking up and clearing the cobwebs, I began lining up the usual suspects on my differential. Was this tumor lysis syndrome, ATN, or perhaps even a manifestation of his underlying CLL, causing either obstruction or direct infiltration of the renal parenchyma??

His evaluation however was not what I anticipated. He looked and felt well, having no complaints with the exception of the iatrogenic-induced hourly bowel movements he was having. He was euvolemic, normotensive, and overall had an unremarkable exam. I confirmed he had no concerning findings on EKG, and pertinent lab values are listed:

Wbc- 270,000, Hgb- 11.3 g/dL, plt- 99,000, uric acid- 6.7 mg/dL, LDH- 690 U/L, Creat.- 1.1 mg/dL, calcium- 8.5 mg/dL, Phosphorus- 4.8 mg/dL, Potassium- 9.3 mmol/L.

The story just wasn’t adding up, so I went to the literature and performed a search on CLL and hyperkalemia, and came across this interesting publication in AJKD…

First described in the 1950s, pseudohyperkalemia is defined as a spurious elevation of the serum potassium, occurring when potassium is released in vitro from cells in a collected blood sample. This may be seen in a variety of myeloproliferative disorders, typically those with marked leukocytosis or thrombocytosis, or as a result of improper collection technique (fist clenching during phlebotomy, a delay in the processing of the sample, or even the use of a pneumatic tube transport system). For a quick review look at Nate's prior post.

Pseudohyperkalemia in cases of leukemia is attributed to the fragility of the cell membrane causing lysis of cells and a falsely elevated potassium reading. This process can be exacerbated by the use of a pneumatic tubing system, as described in several case reports in the literature. In one particular instance, a femoral dialysis catheter was placed and the patient was initiated on hemodialysis with a potassium-free dialysate, resulting in a potassium level of 2.3.

In this patient, blood samples were obtained 45 minutes into dialysis and processed by several different methods.

1. vacutainer draw from a venous catheter into a heparin/lithium tube, pneumatic tube transport (the same as the initial sample).
2. venous sample draw into a heparinized arterial blood gas syringe (no lithium), ran in the ICU machine.
   
3. vacutainer draw from venous catheter into a heparin/lithium tube, walked to the laboratory
4. venous draw into a heparinized arterial blood gas syringe (no lithium), walked to the laboratory.
5. venous draw with a syringe (no vacutainer), poured gently into a heparin/lithium tube, and walked to the laboratory.

You can see that the primary factor responsible for the falsely elevated potassium in this case was the use of the pneumatic tubing system.

Repeated specimens sent the following day confirmed the diagnosis of pseudohyperkalemia, with a pneumatic tube-transported specimen demonstrating a potassium of 10.3 mmol/L and a specimen that was drawn at the same time and walked to the lab demonstrating a level of 5.1 mmol/L.

The take-home message- While psuedohyperkalemia is an unusual and rare occurrence, it is important to be aware of as practicing nephrologists. Missing this diagnosis certainly has clinical implications and can subject patients to unnecessary risk and harm, so always be aware of blood that has been shaken and stirred.

Justin Westervelt, MD

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Femoral versus Jugular, part two

I have always been told that the jugular veins are preferable over the femoral veins when inserting temporary dialysis catheters. Various reasons are put forward for this including increased risk of infection and poor function of femoral catheters due to factors such as recirculation and frequent clotting. A previous post by Nate discussed the Cathedia study in which 750 bed-bound patients were randomized to receive a femoral catheter or a jugular catheter for dialysis. There was no difference in rates of infection as measured by catheter tip colonization or documented line-related bacteremia in the two groups. The authors’ only reservation was that in patients with a higher BMI, a jugular catheter was preferable. In contrast, in patients with a BMI less than 24.2, the use of a femoral catheter was associated with less infections. So much for the first complaint.

So, what about the risk of poor function associated with femoral catheters? In order to determine whether catheter site had any influence over dialysis performance, a paper was recently published in which the authors performed a secondary analysis of the data in the Cathedia trial. The primary endpoints were catheter dysfunction – defined as an inability to achieve adequate blood flow requiring catheter replacement, dialysis sessions delivered, URR and CRRT downtime. Overall, catheter dysfunction occurred in 10.3% of the femoral group and 11.1% of the jugular group. Comparing LIJ to RIJ, the risk of dysfunction was 6.6% on the right as opposed to 19.5% on the left, significantly higher then in the femoral group. There was no difference in URR, number of sessions or CRRT downtime between the two groups. The authors suggested that when choosing a site for vascular access, you should think – RIJ → Femoral → LIJ.

Nate in his previous post came to the conclusion that the original study would not necessarily change his practice although it made it easier to justify the use of femoral lines. This new paper seems like one more piece of evidence that might make me change mine

Hot peppers for hypertension?

An interesting article was published in the August 4th edition of Cell Metabolism. I'm always intrigued when common food ingredients are used to modulate biological systems. This article explores the effect of capsaicin on blood vessel tone. Capsaicin (or 8-methyl-N-vanillyl-6-nonenamide) is what makes "hot peppers" taste hot. This is achieved by activating a particular TRP channel (see Lisa's or Nate's prior post on TRP channels) called the TRPV1 channel. Capsaicin activates the TRPV1 channel and leads to an increase in intracellular calcium. This, in turn, causes the release of several neuropeptides such as substance P or calcitonin gene-related peptide. When a hot pepper in eaten, these changes in sensory nerves leads to the sensation of pain and local heat production.

What other tissue types express TRPV1 channels? And what role do these receptors play in patho- and physio-logical states? It has been previously demonstrated that TRPV1 channels are present in blood vessels. This study demonstrates the presence of TRPV1 in cultures endothelial cells as well as expression in the endothelial layer of an intact vessel. However, there have been a few often contradictory articles published about the acute actions of capsaicin on the blood pressure. Several investigators have shown a relaxing effect of capsaicin in various isolated vessels of pigs and rats. On the other hand, it has also been shown that TRPV1 activation causes vasoconstiction in vessels.

This study demonstrated that chronic TRPV1 activation by capsaicin led to enhanced production of the vasodilatory substance nitric oxide by endothelial cells. After performing several in vitro studies to verify this finding, the investigators fed spontaneous hypertensive rats a diet rich in capsaicin for 7 months and measured blood pressure. This led to a 15-20mmHg decrease in blood pressure as measured by radiotelemetry. However, this decrease in blood pressure was only evident after 4 months of treatment. An excellent editorial written by Dr. Sessa goes into more detail about this study. In conclusion, this is an interesting and provocative study. Much more research is needed before we can offer capsaicin as a therapy for hypertension. But, this could potentially lead to novel therapies aimed at activating the TRPV1 channel. It is still unclear exactly how capsaisin lowers blood pressure in SHR rats. It is likely that other systems are affected by chronic TRPV1 activation that can affect blood pressure. Such as the sympathetic nervous system or the renin-angiotensin system. For now, I'll keep enjoying my yearly hot pepper garden. I'll be interested to see where this research goes from here.

Doc, I am very sensitized!

Another day of transplant clinic… I heard from my attending that a couple is here for a second opinion about a kidney transplant. The husband is a 60 yo male with ESRD 2/2 PKD who had a previous transplanted kidney about 10 years ago that failed last year. Due to persistent fevers, he underwent a nephrectomy of his allograft recently. On revaluation for a second transplant 1 month later, he was found to have a PRA of 98% and also positive cross-match for B and T cells against his son. His physician was not very excited about attempting another transplant and he was looking for additional recommendations.

I feel that dealing with highly sensitized patients have become very common and UNOS reports that more than 25% of patients on the waiting list are sensitized and of those with PRA >80%, only 8% of patients will ever be transplanted! Today, we will discuss some of the terms used in describing sensitized patients and on my next blog will focus on the management of these patients.

The Panel of reactive Antibody (PRA) is a screening test that can tell you how sensitized a potential transplant recipient is to HLA antigens in general. The source of HLA antigens are usually a combination of B and T cells from a panel of donors selected to represent commonly found HLA antigens in the local population. Once the serum of the recipient is added followed by complement, cell lysis detection is performed and the results are represented as the percentage of panel cells that are killed by the serum. The PRA does not tell you if you have antibody against any specific donor, but it can estimate how sensitized you might be to potential donors in your community and predict the likelihood of finding a compatible donor. For example, a PRA 70% suggests that 70% of donors will likely be unacceptable for the tested patient due to the presence of anti-HLA antibodies.

On the other hand, the crossmatch can specifically test if the recipient has any antibodies against the donor. Our patient above was very sensitized with a PRA of 98% and also had specific anti-HLA antibody against his donor. A positive crossmatch against B and T cells suggest class I anti-HLA Ab, while the presence of only Abs against B cells indicates class II. IgG antibodies against class I are the most important for transplantation. IgM antibodies usually represent autoantibodies and are not considered true sensitization. Their activity can be removed either by heating the serum to 55 degrees C or by using DTT reducing agent. If crossmatch is positive, the lab will also usually run recipients' serum with his/her own cells to rule out auto-antibodies.

The crossmatch assays available differ in their sensitivity to detect Abs and most centers perform the classic cytotoxicity (CDC) assay, while others also perform a flow cross-match and/or luminex. In addition to determining the positivity, these assays can tell you how strong the reaction is by reporting the titer. Regardless of the test used, highly sensitized patients are often crossmatch positive to multiple potential donors and require a zero antigen mismatch allograft to increase success. These patients are therefore relegated to the deceased donor waiting list and have a very low rate of eventual transplantation.

For this reason, desensitization against preformed HLA antibodies should be considered. The titers of antibodies are important in determining how feasible a desensitization might be. We will discuss on the next blog the current recommended desensitization protocols according to anti-HLA titer levels and other potential options, focusing on our case above as an example.

Addendum: Your lab might perform additional modifications of the CDC assay: Amos-modified CDC to eliminate clinically irrelevant Abs and AHG-modified CDC, in which anti-human globulin (AHG) is added to induce cross linking and increase sensitivity.

Tubulointerstitial disease

ANATOMY

The tubulointerstial tissue is composed of cortex and medulla. The cortex has type 1 cells resembling fibroblasts and produces Epo. Type 2 cells in the cortex resemble dendritic cells capable of Ag presentation. Furthermore the cortex contains types 1 and 3 collagen. The medulla has type 1 cells which produce prostaglandins (e.g. COX-2), type 2 cells resembling lymphocytes and type 3 cells located near the vasa recti with unclear function. Histopathologically AIN represents inflamed and edematous interstitium. The phases following such injury include tubular cell proliferation and dilatation, cast formation, atrophy and/or apoptosis and fibrosis.

CAUSES

Tubulointerstitial disease can occur within days to weeks (acute) or within months to years (chronic). There are a lot of (secondary) causes of TIN (tubulointerstitial nephritis) which include:

- Infections: pyelonephritis, vesicoureteral reflux, viral infections (CMV, HCV, HIV, etc.)
- Drugs: NSAIDs, many antibiotics, diuretics, lithium, cidofovir, calcineurin inhibitor, cisplatin, ifosfamide, etc, etc,…
- Toxins: lead, heavy metals, (Chinese) herbs, etc.
- Hem/Onc: multiple myeloma (MM), lymphoproliferative diease, light chain disease, sickle cell disease (SCD), etc.
-Immune-mediated: Sarcoid, Sjogren, SLE, TINU (TIN with uveitis), TIN with hypocomplementemia, etc.
- Genetic: Dent disease, cystinosis, hyperoxaluria, autosomal-dominant hypoparathyroidism, karyomegalic IN, etc.
- Metabolic: hypokalemia, hypercalcemia, urate nephropathy, etc.
- Miscellaneous: Balkan nephropathy, radiation, IBD, etc.

Reference: Braden et al, AJKD, 2005, 46(3)

RENAL FEATURES OF TUBULOINTERSTITIAL NEPHRITIS (TIN)

Electrolyte/Acid-Base disorders:
- Proximal RTA/Fanconi syndrome (MM, SS, Dent disease, cystinosis)
- Distal RTA, type I & type IV: (PN, VUR, Li, Lead, MM, Light chains, SS, SLE)
- Sodium wasting (any disorder)

Clinical syndromes:
- Kidney stones (hypercalcemia, urate, sarcoid, IBD)
- Nephrogenic DI (Li, Cisplatin, hypokalemia, hypercalcemia, Dent)
- ARF (PN, AN, Li, CNI, Cisplatin, Myeloma, Lymphoma, SLE, XRT)
- Papillary necrosis (PN, analgetic nephropathy)

DRUG-INDUCED INTERSTITIAL INJURY

- Time from exposure to development varies
- Sediment: pyuria, WBC casts, eos, hematuria/proteinuria
- One third of patients present with classic symptoms including fever, rash, arthralgias, eosinophilia
- Histologically inflammation with lymphos, monos, eos, plasma cells
- Mechanism: drugs bind to or mimic tubular Ag and cause immune reaction likely through T cells. This causes tubulitis through proinflammatory and profibrotic cytokines
- Most frequent drugs involved: PCN, cephalosporines, phenytoin, thiazide, lasix, cimetidine, ranitidine, rifampin, allopurinol, INF, NSAIDs, COX2 inhibitors (rofecoxib), clarithromycin, PPIs, etc., etc.
- Treatment: DISCONTINUE drug; supportive measures such as maintaining euvolemia andavoidance of nephrotoxins
- Steroids: may help (shorten the time of recovery), but there is no proven benefit in overall outcome

Reference: Choudhury et al, Nat Clin Pract, 2:2, 2/2006

TIN AND TINU (TIN WITH UVEITIS, picture provided on top)
- First described in 1975 by Dobrin and colleagues. Over 200 cases were reported in the literature.
- Patients are mainly adolescents, male to female ratio is 1:3 and median age of onset is 15 (with extremes of 9-74 years of age)
- Risk factors are unclear. Both antibiotics and NSAIDs have been implicated
- TINU Typically presents with ARF and often includes fever, N/V, weight loss, anemia and elevated ESR
- Anterior uveitis (=Iritis) can occur prior, concurrently or after TIN ! In 58-72% of cases it occurs bilaterally.
- Histology often shows activated memory T-cells. An association with HLA-DRB1 has been associated in the literature.
- Adolescents often have spontaneous remission. Steroids often are useful in improving renal function, however Uveitis frequently relapses

References:
Dobrin et al, Am J Med, 59:325, 1975
Takemura et al, AJKD, 34:1016, 1999
Kadanoff et al, J Clin Rheum, 10:25, 2004

Should we give up on anti-B-cell antibody therapy in the treatment of lupus nephritis?

For those of us managing patients with active lupus nephritis, the promise of a safe new therapy five years ago - anti-CD20 monoclonal antibody therapy against B cells- seemed like a breath of fresh air. A number of case controlled series of relapsing lupus nephritis (LN) were published highlighting the efficacy of Rituximab, anti-CD20 B cell depleting monoclonal humanized antibodies, in triggering remission. Indeed my own clinical practice, and that of several colleagues, has shown quite remarkable remissions in some patients seemingly brought about by Rituximab in patients who had relapsed on standard therapy including Cyclophosphamide (CYC). In late 2008 the EXPLORER study was reported, in which patients with non-solid organ lupus received Rituximab in addition to standard therapy, and saw no benefit in BILAG (lupus activity scores). Although the study had limitations, and excluded patients with LN, some questions were raised about Rituximab, given the widely accepted efficacy of MMF in Lupus and LN. Last year the LUNAR study reported 144 patients with first presentation LN (class III or IV). In addition to prednisone and MMF, patients were randomized to either 4 doses of Rituximab over 1y or placebo. Although there was a clear trend toward benefit in the Rituximab group, and it was well tolerated, there were no significant differences in remission rates at 52 weeks (Furie et al ACR/ARHP meeting 2009; abstract 1149).


Does this mean that Rituximab does not work and we should not use it? I think that this is not the case:

1. We should reflect on how MMF (which also has anti-B cell activity) has become a widely accepted, and somewhat surprising, therapy. Initially MMF was found to be effective in case controlled series of relapsing patients. Then, in a RCT from Hong Kong, it was tested head to head with CYC (which has anti-B cell activity) in newly-presenting patients with class III and IV LN disease, and proved equally efficacious as CYC at 1yr and 5yrs. This landmark study was equivalent to, but different from, the LUNAR study. Rituximab was given in addition to prednisone + MMF, not head to head with prednisone + MMF as in the LUNAR study. We will never know whether MMF would have added benefit beyond that of prednisone + CYC in the Hong Kong trials. The LUNAR study design may have therefore been flawed, by drawing on experience from cancer trials in its design, where therapies are added to standard regimes (rather than in the Hong Kong LN trial where therapies were studies head to head).
2. Recently a trial of anti-B cell antibody therapy (BLISS-76) using Belimumab, which inhibits the activity of BLys (an activator of B cells), reported positive results in non-solid organ lupus (analogous to the EXPLORER trial). While there will be differences in the efficacy of Rituximab and Belimumab, the differences in the trial design may prove to be more important in providing evidence of efficacy for this anti-B cell therapy. It suggests that anti-B cell therapy may still be a good option for lupus.
3. Without doubt SLE (and lupus nephritis) is not a single disease, rather syndromes with multiple genetic predispositions. It is clear that some patients respond well to one therapy, whereas others respond better to a second regime. It is also true that patients receive different types of therapy during the course of their disease as their responsiveness changes.
4. Rituximab is probably the safest immunotherapy we have for lupus.

In my opinion, Rituximab remains a therapeutic option for relapsing LN, as it is safe and is efficacious in many of these patients. It behooves us to consider carefully whether additive trials, which are now the standard in cancer therapy, are appropriate in lupus nephritis and whether we can justifiably withhold MMF from patients with active disease for a potentially better therapy.

Mmm, let's try rituximab

Mixed cryoglobulinemia (MC) is a systemic vasculitis in which B cell clones produce IgM with rheumatoid factor activity. The disease can range in severity from isolated skin lesions to full blown renal and neurological involvement. Most patients are HCV positive although about 25% have essential mixed cryoglobulinemia (EMC) where no underlying cause is found. Traditional therapy for MC included treating the underlying cause along with cytotoxic drugs but this is associated with significant complications.

We recently had a patient with EMC and significant renal involvement who we decided to treat with rituximab. Rituximab is a monoclonal antibody directed at CD20, a transmembrane protein expressed on B lymphocytes, which has been shown to delete expanding clones of B cells. There is growing evidence that rituximab is effective in treating MC in HCV-positive and HCV-negative patients. A recent meta-analysis found that complete and partial responses to rituximab therapy were noted in 80-93% of patients with MC. Relapses were more common in the HCV-positive group with 39% relapsing within 12 months – probably as a result of the ongoing presence of the viral antigen. The doses and treatment lengths varied significantly among the studies and there is no definite treatment protocol that has been shown to be universally effective as yet.

There are some potential complications associated with rituximab therapy in these patients. It has a tendency to increase HCV viremia potentially leading to worsening liver disease although a recent study found it to be effective and safe in a group of patients with severe liver disease. Another potential complication arises from the fact that rituximab is an IgG1kappa chimeric antibody as it appears to bind to the IgM paraprotein in some cases leading to the deposition of more immune complexes and worsening of the vasculitis. This complication is seen particularly in those treated with high dose rituximab (1g) and suggests that lower dose therapy (375mg/m2) may be more appropriate.

Our patient responded well to rituximab therapy. He received four weekly doses of 375mg/m2. His creatinine has fallen from a peak of 3.6 to 1.4 and his proteinuria has resolved. It will be interesting to see if he remains in remission over the coming months.

So MC is added to the growing list of renal diseases that can be effectively treated with rituximab. See previous blog posts on the use of rituximab in patients with ANCA-associated vasculitis, transplant glomerulopathy, lupus nephritis and membranous nephropathy.

A note of thanks to Dr Hamburger for his help.

Water treatment in dialysis- more than a Brita filter

And now for something totally exciting—a post on water treatment in dialysis. Dr Daniel Coyne of Washington University gave a great review on this topic at the Brigham Renal Board Review course this week. Here is the basic process of water treatment in HD:

1) water passes through filters for particle removal
2) it then passes over activated carbon, which removes chlorine and chloramines
3) next is a cation exchange resin that serves to “soften” hard water, i.e. exchange Ca and Mg for Na
4) then: reverse osmosis. Pressure is applied to the water and pushes it over a polyamide or cellulose acetate membrane. This process rids the water of organic matter, bacteria, and endotoxins.
5) next step: deionizers, resins that remove cations and anions.
6) water is then irradiated to kill any remaining pathogens.
7) then it is ultrafiltered to remove any remaining bacteria, viruses, and pyrogens.

Water is then continuously circulated to avoid stagnation, and siphoned off to different dialysis stations during treatment.

If you see the following signs in patients at a particular dialysis unit, consider the following water treatment problems:

Anemia- aluminum, chloramines, copper, zinc
Bone disease- aluminum, fluoride
Hemolysis- chloramines, copper, nitrates (3 C's from Nate's prior post)
Hypertension- calcium, sodium
Hypotension- bacteria, endotoxins, nitrates
Metabolic acidose- low pH, sulfates
Encephalopathy- aluminum
Nausea/vomiting- bacteria, endotoxins, low pH, nitrates, sulfates, zinc

Many thanks to Dr Coyne for the shameless pirating of several of his slides.

Adult-Onset dense deposit disease

We recently saw a case of adult-onset dense deposit disease (DDD) at pathology conference. DDD is rare, affecting 1-3 per million people. For historical reasons it has been classified under the membranoproliferative subgroup of disease patterns (as type 2), but many voices within pathology are calling for this to be changed.

DDD primarily presents in childhood with the nephrotic or nephritic syndrome. However, it can have a wide range of other clinical presentations, including sterile pyuria, isolated macroscopic hematuria, microscopic hematuria with subnephrotic range proteinuria, and isolated proteinuria. Most patients have low C3 levels; C4 is usually normal and around 80% have a detectable C3 nephritic factor. As a rule of thumb, C3 is nearly always depressed in children, whereas this occurs less than half the time in adult presentations.
Extra-renal manifestations include formation of retinal drusen and development of acquired partial lipodystrophy. Lipodystrophy is highly correlated with the presence C3 nephritic factor, with detectable levels in almost all cases.

DDD is thought to be caused by excess activation of the alternative complement pathway. In the alternative pathway, the normal cascade is initiated by cleavage of C3 to C3a and C3b. C3b joins with Factor B and properdin to form C3 convertase. C3 convertase causes further cleavage of C3, increasing the amount of C3b available to form C5 convertase. C5 convertase cleaves C5 to C5a and C5b. The former has a chemoattractant function; the latter contributes to formation of the membrane attack complex. Factor H serves to regulate this pathway by promoting degradation of C3 convertase and C5 convertase. It also combines with Factor I to inhibit C3b.

Thus, it is thought DDD can arise from two main events: formation of a C3 convertase stabiliser (C3 nephritic factor) or loss of Factor H (mutation v acquired). The formation of excess complement components allows deposition in the GBM and incitement of an inflammatory reaction.
The diagnosis is made by examination of renal histology. Interestingly, only 25-44% of cases present with a membranoproliferative pattern of injury. Immunofluorescence is generally positive for C3 in areas of deposits. Immunoglobulin staining is typically negative, which helps distinguish it from MPGN type 1. The pathognomonic changes are seen in electron microscopy – abnormal electron-dense deposits in the GBM.
Finally, a first presentation of DDD in an adult should always prompt a search for an underlying plasma cell dyscrasia, which was discovered in this case.

A review of the complement cascade by Nate can be found here.


Finnian McCausland M.D.

Warfarin-induced AKI

We have recently posted about problems using warfarin in renal patients. On a similar note, I was recently involved in the care of a 58-year-old African-American patient who presented with oliguric AKI and a supratherapeutic INR level of 14.9 while on warfarin therapy for pulmonary embolism. Although AKI was probably secondary to ischemic ATN from massive bleeding (requiring 11 units of PRBCs), this patient made me wonder whether warfarin could itself cause AKI in the absence of significant hemodynamic changes.

It has been suggested that warfarin may induce AKI by causing glomerular hemorrhage and renal tubular obstruction by RBC casts. The first report by Abt, et al observed glomerular hematuria in a patient with excessive warfarin anticoagulation with underlying structural abnormality of glomerular basement membrane, suspected warfarin-induced glomerular hematuria. This finding was also noted by Kabir et al and Brodsky et al. subsequently reviewed renal biopsies from 9 patients with elevated serum creatinine level (mean, 4.3±0.8 mg/dL) and abnormal INR (mean, 4.4±0.7 IU) after excluding acute/active glomerulonephritis. INR was normalized before the kidney biopsy. The biopsy specimens revealed RBCs in both Bowman spaces and tubules. The occlusive RBC casts were mostly localized to distal nephron segments. The presence of RBCs was unlikely related to the biopsy procedure as the distribution of RBCs was within the nephron, non-uniform, and not in the interstitium or around the edges of the biopsy specimens. Moreover, the presence of occlusive RBC casts compressing tubular epithelium suggested glomerular hematuria. All of these patients had underlying kidney disease. Recovery was incomplete in six of nine patients. Based on this review, it seems that warfarin is unlikely to cause AKI in patients with normal renal parenchyma. However, elderly patients with underlying kidney diseases may be at risk for developing warfarin-associated AKI by this mechanism.

In addition to this potential renal complication of warfarin therapy, there were 2 case reports of warfarin-induced AIN by Volpi et al. and Kapoor et al. The latter case reports a patient on warfarin for 2 months for DVT who presented with AKI, supratherapeutic INR and skin rash. Renal biopsy revealed AIN and punch skin biopsy showed LCV with high eosinophil count, highly suggestive of drug-induced reaction after a negative comprehensive work-up and the absence of other recent medication changes. Warfarin was withdrawn and the patient’s renal function began to resolve upon discharge. Spontaneous cholesterol embolization is also widely reported in patients with diffuse atherosclerosis on anticoagulation.

In summary, it appears that in patients with pre-exiting CKD, warfarin may precipitate AKI via either glomerular hemorrhage and intra-tubular obstruction, AIN, spontaneous cholesterol embolization, in addition to hemodynamic change secondary to massive blood loss. This should be borne in mind in cases of AKI in patients taking warfarin, when diagnosis is unclear.

Boonsong Kiangkitiwan, M.D.

Chronic dialysis exposure during nephrology fellowship

Much of medical residency training in the US is centered in the hospital. This is also true of many of the fellowship programs in internal medicine. As we have seen a continual increase in the number and acuity of patients admitted to the hospital. The number of house staff have remained static. The busy nephrology fellow spends a majority of time rounding on inpatient services, answering consults or arranging renal replacement therapy for patients already on some form chronic dialysis who happen to be admitted to the hospital. Typically, outpatient exposure to CKD and transplant come during the fellow's weekly continuity clinic. However, obtaining adequate exposure to patients on some form of chronic dialysis performed either in-center or at home can be challenging. An online survey of 133 recent nephrology graduates (2004-2008) published in the March 2010 CJASN showed that 81% were well-training in caring for primary care issues in patient with CKD/ESRD. They also showed that 80% felt that they were well-trained/competent in in-center hemodialysis, but 60% and felt that little or no training was offered in home HD. This same survey showed that 78% had little or no training in dialysis unit directorship. The majority of respondents to this survey were recent graduates (>2 years since fellowship).

RFN decided to conduct a poll to see whether or not nephrology fellows were well-prepared to attend chronic outpatient hemodialysis clinics. Our results were a little different than the one published in CJASN. Out of 63 total respondents to our poll, only 14 or 22% felt that they were 100% prepared for chronic hemodialysis clinics. 25, or 39% felt that they had good exposure, but would like more. Interestingly, 22 or 34% of respondents indicated that much more exposure was needed. What do we make of this poll? It is clear that nephrology training is heavily centered in the hospital. How do we shift our focus out of the hospital to gain not only more exposure to chronic "stable" patients, but more longitudinal continuity of care? This is really where learning happens. Following patients on a long term basis is the only way to learn about the ever changing nutritional, access related, weight adjustment etc. etc. etc. issues that patients on chronic renal replacement therapy have. I would be interested to hear about the different outpatient experiences fellows from programs around the US and world have. We typically spend 6 consecutive months dedicated to following a group of patients on a given dialysis shift with the close supervision of an attending. Patients are seen weekly while on dialysis. Fellows with an interest in home-hemodialysis or nocturnal dialysis can choose to follow these patients as well. This allows for the fellow to have a great deal of continuity of care. In conclusion, from the results of the RFN poll it appears that nephrology fellows are wanting more exposure to chronic hemodialysis. Trying to balance each of the different areas of nephrology education can be difficult, but chronic dialysis needs to be a centerpiece of any successful fellowship program.

I think we need to have a talk about your diet

The picture above comes from a case report in KI where a PD patient presented with hypertension and edema. She was normally compliant and a plain film of her abdomen was performed to make sure that her catheter was properly sited. Densely radiopaque material was found to be present throughout her colon. There was no history of recent contrast studies and she was asymptomatic. What could cause this radiographic appeareance?

The answer to this mystery lay in her medications. She had been started on the phosphate binder lanthanum carbonate 3 months previously. Lanthanum is a rare earth metal which lies next to barium on the periodic table and has a high affinity for phosphate. It has little systemic absorption and low solubility and remains largely in the intestine after ingestion. It is a high density material with a density between that of bone and metal. The CT above shows lanthanum tablets in the stomach which have a higher density (3000HU) than the radiocontrast in the aorta (450HU). This accumulation appears to cause no ill effects and disappears once the drug is stopped or with the use of laxatives. The main issue is that it may interfere with the interpretation of xrays and radiologists should be informed that a patient is on this drug prior to abdominal imaging in order to prevent confusion.

Boost it up!

Dealing with patients on dialysis can be challenging. In addition to the management of many comorbidities, nephrologists have to go down a list similar to a pilot’s checklist. Those include dialysis adequacy, access, electrolyte balance, fluid status, BP control, anemia management, Ca/PO4/vitD/PTH,… For last, when time allows, they might have room for the nutritional status box.

Protein-energy malnutrition (PEM) is very common in ESRD reaching close to 50% of patients, depending on the parameters used. Why is it important? Well, PEM is a powerful predictor of morbidity and mortality. Ballpark, for every 1g/L decrease in albumin, a 10% increase in mortality risk has been reported.


Its etiology is believed to be multifactorial:

1. Inadequate nutritional intake due to taste abnormalities, gastropathy/enteropathy, anorexia and psychosocial (depression, poverty or ETOH abuse).
2. Dialysis-related nutrient losses: about 10g of aminoacids are lost after each HD session!
3. Catabolic state due to inflammation/uremia, metabolic acidosis and dialysis procedure (exposure of blood to HD membrane).
   

Without any complicated malnutrition score, we are usually able to recognize malnourished patients by their physical appearance and some metabolic abnormalities like low BUN/Cr preHD, low phosphate, low cholesterol, elevated ferretin and low Hb. The normalized protein catabolic rate can also help.

So, what can we do for that?

1. Improve dialysis adequacy: e.g. daily hemodialysis has been shown to improve nutritional parameters. But at this time your dialysis nurse or patient might not agree with that…
2. Oral nutrient supplementation: strong data supporting the use of these agents. If your patient’s albumin is below 3.5, you should be thinking about that! Choice should consider the price, palatability and lactose tolerance. Nepro is a classic – one can contains approx. 17g of protein, 23g of fat and 53g of carbs (475 kcal) – pack of 24 for $69; compared to regular protein cans (e.g. Boost), they have less phosphate and potassium. Protein powder without flavor is also a great choice since it can be added to any fluid, improves palatability and cost less. Even sports protein bars have been shown to be acceptable protein sources. Compliance is a major issue and many studies have given the supplements before/after HD session.
3. Correction of metabolic acidosis with PO bicarbonate.
4. Appetite stimulants: megestrol has been used on cancer patients but side effects are frequent in HD patients and is usually not recommended.
5. Finally, intradialytic total parenteral nutrition should be considered only for patients unable to use the GI tract and severely malnourished.
   

Also check Dr Rubin’s blog on hidden inflammatory state for reversal conditions you should be considering as well...

Board Review; Pregnancy answer

Each of the following choices is expected to occur during pregnancy except for A and D. Let’s go through each of the possible choices.

A. This in partially incorrect. Hyperventilation (with resultant hypocapnea, not hypercapnea) occurs during pregnancy and is largely a consequence of stimulation of the respiratory center via progesterone. Therefore, in pregnancy you typically see a chronic respiratory alkalosis which is compensated by renal excretion of bicarbonate. Luckily, in pregnancy the oxygen-dissociation curve is not dramatically altered due to increased 2,3 DPG levels in pregnancy and normalization of blood pH through renal compensation.

B. This is correct. During pregnancy the intestinal absorption of calcium nearly doubles as early as week 12 of pregnancy and is likely the major maternal adaptation to meet the fetal need for calcium. As intestinal calcium absorption increases, extra calcium is either deposited in the fetal skeleton, the maternal skeleton or is excreted by the kidneys. Renal calcium excretion is increased as early as the 12th week of gestation and 24 hour urine values (corrected for creatinine excretion) can exceed the normal range. Conversely, fasting urine calcium values are normal or low, confirming that the hypercalciuria is a consequence of the enhanced intestinal calcium absorption. Pregnancy is recognized as a risk factor for kidney stones and the absorptive hypercalciuria of pregnancy is one reason for this.

C. This is also correct. During pregnancy kidney size can increase by 20%. This increase in kidney size also corresponds to an increase in GFR and renal blood flow.

D. This is incorrect. Remember that filtration fraction (FF) is the ratio of glomerular filtration rate (GFR) to renal blood flow (RBF). The filtration fraction represents the proportion of fluid reaching the kidneys which eventually passes into the tubular lumen. In pregnancy, although the GFR is increased, RBF is increased to a greater extent. Therefore, FF actually decreases in pregnancy. Since the increase in GFR and RBF is not associated with an increase in FF, there is no risk of secondary FSGS in pregnancy. This is supported by small studies.

E. This is correct. During pregnancy, urinary protein excretion increases from normal nonpregnant levels of 60–90 mg/24 hours to 180–250 mg/24 hours in the third trimester. Even if slightly increased during pregnancy, urine protein excretion rarely reaches levels that are detected by usual screening methods, such as 1+ on urinary dipstick (i.e., 30 mg/dL, which is roughly equivalent to 300 mg in 24 hours). Although the mechanism for this possible increase has not been established, it seems likely that absorption of filtered protein in the proximal tubule is reduced.

F. This is correct as well. During pregnancy, physiologic changes occur in volume- and osmoregulation that effect plasma osmolality and sodium concentration. During a normal pregnancy, the average plasma osmolality decreases by 5-10 mmol, and the sodium concentration is decreased by 5 mmol/l. This drop in plasma osmolality has been explained by a phenomenon termed ‘reset osmostat’. A ‘reset osmostat’ is when the osmotic threshold above which ADH-release and a thirst stimulus occur changes. This threshold is decreased to a lower steady state value during normal pregnancy. The mechanism that causes the reset-osmostat phenomenon is unknown.

On a lighter note, the “Gross Clinic” has completed its restoration and is currently on exhibit at the Philadelphia Museum of Art. It is a must-see for any devotee of medicine.
Michael Lattanzio DO